Psychiatric diseases are thought to be due to dysfunctions in monoaminergic neuronal systems, particularly those involving serotonin (5-HT) and dopamine (DA).
Anxiety is associated with increased activity in 5-HT systems. In animals where 5-HT has been depleted, benzodiazepine anxiolytics are not active in anti-anxiety assays that they otherwise are effective in. Serotonin neurons have autoreceptors that, when activated by agonists, depress firing rates of 5-HT cells. These receptors are of the 5-HT.sub.1A subtype. Because they depress 5-HT neuronal activity, it can be expected that 5-HT.sub.1A agonists will be an effective anxiolytic. Clinically, 5-HT.sub.1A agonists have demonstrated anxiolytic properties. The drug Buspirone, is the only currently available marketed 5-HT.sub.1A agonist having anxiolytic activity. This compound antagonizes dopamine receptors at the same dose it stimulates 5-HT.sub.1A receptors. A similar drug, Gepirone, also has dopamine antagonist properties. These dopamine antagonist properties reduce the clinical utility of these compounds because long term treatment with dopamine antagonists can produce tardive dyskinesia.
Depression is a psychiatric condition thought to be associated with decreased 5-HT release. Most anti-depressants potentiate the effects of 5-HT by blocking the termination of activity through re-uptake into nerve terminals. Since some 5-HT.sub.1A receptors are activated postsynaptically by 5-HT, 5-HT.sub.1A agonists may also be anti-depressants. Since the postsynaptic 5-HT.sub.1A receptor may be less sensitive than the autoreceptor, high doses of 5-HT.sub.1A agonists, particularly very effective ones (i.e., those causing greater stimulation of the 5-HT.sub.1A receptor, a parameter referred to as "efficacy"), can be expected to be effective anti-depressants. Gepirone has already been demonstrated to have ameliorative effects on some depressive endpoints in some patients.
Serotonin is also involved in the regulation of feeding and sexual behavior and in cardiovascular regulation. Thus, 5-HT.sub.1A agonists may be useful in treating overeating and sexual dysfunction. These compounds have been shown to alter feeding and sexual behavior in animals. 5-HT.sub.1A agonists are also known to depress sympathetic nerve discharge and thus lower blood pressure. Thus, they may be useful in treating hypertension, congestive heart failure (by reducing cardiovascular afterload) and cardiac arrythmias (by removing sympathetic drive to the heart).
The compounds of the present invention have a variety of effects at the 5-HT.sub.1A receptor, and offer a variety of utilities associated with those activities.
The search for new CNS active compounds is focused on finding compounds with selective 5-HT.sub.1A receptor agonist effects without detrimentally influencing central dopamine receptors. Compounds resistant to liver metabolism would be expected to have a greater oral bioavailability and therefore a significant therapeutic advantage over rapidly metabolized compounds.